Tumor necrosis factor is a polypeptide cytokine involved in inflammation and the acute phase response. TNF-alpha is present in larger quantities in persons with rheumatoid arthritis or Crohn's disease. It is also involved in Juvenile Idiopathic Arthritis (JIA), Psoriatic Arthritis (PA), Ankylosing Spondylitis (AS), Ulcerative Colitis and Plaque Psoriasis. Direct inhibition of TNF-alpha by the biological agents has produced significant advances in rheumatoid arthritis and other auto-immune disease treatment and has validated the extra-cellular inhibition of this pro-inflammatory cytokine as an effective therapy. One such biological agent is Adalimumab.
Adalimumab (Anti-TNFα antibody), marketed as HUMIRA® by Abort Inc., is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Adalimumab was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgG1 constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.
Generally, proteins have a very short half-life, and undergo denaturation (such as aggregation, dissociation, and adsorption on the surface of vessels) upon exposure to various factors such as unfavorable temperatures, water-air interface, high-pressure, physical/mechanical stress, organic solvents and microbial contamination. Consequently, the denatured protein loses intrinsic physicochemical properties and physiological activity. Denaturation of proteins is often irreversible, and therefore proteins, once denatured, may not recover their native properties to the initial state.
In the biopharmaceutical industry, the long term storage of proteins, prepared using recombinant DNA technology in aqueous formulations, is generally a difficult task. To overcome the stability problem of proteins in aqueous formulations, therapeutic protein products are made more stable via lyophilization (freeze-drying). Lyophilized products are usually accompanied by sterile aqueous media for reconstitution. After reconstitution, the formulations typically have short useful storage lives, even when stored at low temperatures (e.g., 5° C.). Example of TNF alpha inhibitors which are available in the market in the lyophilized form are Enbrel® and Remicade® and both the compositions should be reconstituted before use.
Typical practices to improve polypeptide stability can be addressed by varying the concentration of elements with the formulation, or by adding excipients to modify the formulation.
U.S. Pat. No. 5,580,856 discloses the stabilization of dried proteins against loss of biological activity in the formulations by adding a reconstitution stabilizer upon rehydration of the dried protein. A kit for producing a formulation by dissolving the dried composition in a solvent containing the reconstitution stabilizer is also described.
U.S. Pat. No. 6,171,586 discloses a stable aqueous pharmaceutical formulation comprising a therapeutically effective amount of an antibody not subjected to prior lyophilization, a buffer maintaining the pH in the range from about 4.5 to about 6.0, a surfactant and a polyol, along with uses for such a formulation.
EP1314437 relates to an invention of stabilized preparations containing an antibody in a glycine buffer and/or a histidine butter and also provides processes for preparing a protein-containing stabilized preparation, comprising adjusting the pH with a basic amino acid or a basic amino acid derivative or a salt thereof.
EP1478394 discloses about the invention that relates to an aqueous pharmaceutical composition suitable for long-term storage of polypeptides containing an Fc domain of an immunoglobulin, methods of manufacture, methods of administration and kits containing same.
U.S. Pat. No. 8,216,583 disclose formulation of human antibodies for treating TNF-α associated disorder. The antibody claimed in the invention is adalimumab. It discloses a liquid aqueous pharmaceutical formulation is described which has a high protein concentration, a pH of between about 4 and about 8, and enhanced stability.
U.S. Pat. No. 8,420,081 discloses an aqueous formulation comprising water and a protein, and methods of making the same. The invention is directed towards the findings that proteins formulated in water maintain solubility, as well as stability, even at high concentrations, during long-term liquid storage or other processing steps, such as freeze/thawing and lyophilization.
Hence, there is a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody which is suitable for therapeutic use to inhibit or counteract detrimental TNFα activity. There is also a need for a stable aqueous pharmaceutical formulation with an extended shelf life, comprising an antibody suitable for therapeutic use which is easily administered and contains a high protein concentration.